The GPR17 receptor is an orphan G protein coupled receptor (GPCR). Members of this project team previously identified the GPR17 receptor as an effector of Forkhead Box O1 (FOXO1) orexigenic signaling in hypothalamic agouti-related peptide (AgRP) neurons. Loss of GPR17 in AgRP neurons leads to increased CNS sensitivity to insulin and leptin, and improved glucose homeostasis. It is hypothesized that inhibition of GPR17 function may increase satiety and improve whole body glucose homeostasis. Currently, there is only one weak antagonist (Pranlukast/ONO 1078) available for GPR17. During this reporting period, a reporter cell line was utilized to conduct high-throughput screening of more than 150,000 compounds for GPR17 antagonism. Hit compounds were cherry-picked and validated in confirmatory and counter assays. Compounds with attractive activity profiles were advanced for additional characterization in cell-based assays and animal studies.